N-alkyl-n-benzhydrylaminoalkyl esters of n, n-dialkylaminoalkanoic acids, their salts and the production thereof



United States Patent N Drawing. 'Applic ationAugust 12, 1954,

Serial N0- 449,495

8 Claims. cued-482 My present invention relates to basic estersof dialkyl substituted amino acids and, more particularly, to N-alkyl- N- benzhydrylaminoalkyl' esters of N,N-dialkylaminoalkanoic acids, their salts and the production thereof.

The compounds which constitute my invention canbe represented by the general basic formula I (lower alkyl) wherein A is a lower alkylene radical and B is a lower alkylene radical separating the carboxy group and the nitrogen atom attached thereto by at least two carbon atoms.

In the foregoing structural formula the three lower alkyl groups can be methyl, ethyl, straight-chained and branched propyl, butyl, amyl and hexyl groups; The radical A is a lower alkylene radical derived from a lower bivalent aliphatic hydrocarbon radical such as methylene, ethylene, propylene, butylene, amylene, hexylene or a polymethyle'ne. radical such as trimethylene, 'tetramethylene, pentamethylene, hexamethylene, and the like. The radical B is of the same type except that at least .two carbon" atoms must separate the carboxyand the benzhydrylamino radical; this excludes the methylene radicaL.

The compounds of my invention are valuable as intermediates in organic synthesis. They are also valuable as medicinal agents and, particularly, as cardioregulatory and hypotensive agents and as specific musculot ropic spasmolytics. They have a powerful papaverine-like action. The quaternary ammonium salts are active ganglion blocking agents.

The bases described above form. salts which are nontoxic in therapeutic dosage with a variety of. inorganic and strong organic acids such as phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, acetic, maleic, .malic,

Example 1 A mixture of 741 parts of diphenylbromomethane, 450 parts of N-methyl-p-hydroxyethylamine, 1600 parts of butanone, and 5 parts of sodium iodide is stirred for 2 hours and then concentrated under vacuum on a steam bath. The residue is rendered alkaline by addition of aqueous potassium carbonate and extracted with ether. This extract is washed with water, dried over anhydrous calcium sulfate, filtered and evaporated. The residue is distilled at 0.5 mm. pressure to yield N-(fi-hydroxyethyD- N-methylbenzhydrylamine at 142-143 C. Y

A solution of 48 parts of N-(B-hydroxyethyD-N- methylbenzhydrylamine in 88 parts of anhydrous thiophene-free benzene is treated with 22.4 parts of chloroacetyl chloride under ice cooling. After subsidence of the initial exothermic reaction, the mixture is refluxed for 10 minutes and cooled. The precipitate is collected on a filter and dried. Crystallized from ethanol, the hydrochloride of the chloroacetate of N-(fi-hydroxyethyl)-N-methylbenzhydrylamine'is obtained which melts f 'at about 191-194 c.

Into a solution of 18 parts of the chloroacetate of N-(B-hydroxyethyl)-N-methylbenzhydrylamine (liberated by alkalinization of the hydrochloride and ether extraction) in 50 parts of butanone, 6 parts of gaseous dimethylamine are introduced. The mixture is then heated for4 hours at C. and permitted tostand at room temperature. After evaporation of the butanone the residue is dissolved in dilute hydrochloric acid, washed with ether, rendered alkaline by addition of potassium carbonate'and extracted with ether. This extract'is dried over anhydrous potassium carbonate, filtered and evaporated and the residue is distilled at 190 C. and 0.8-1.2 mm. pressure.

Treatment of this oil with alcoholic hydrogen chloride yields the water soluble dihydrochloride melting at about 234-235 C. This salt has the structural formula Example 2 The hydrochloride of the chloroacetate of N-(fi-hydroxyethyl)-N-methylbenzhydrylamine is dissolved in water and the solution is rendered alkaline by addition of potassium carbonate and extracted with ether. The free base is obtained by evaporation of the ether. 36 parts of this base are dissolved in 100 parts of butanone and treated with 18 parts of diethylamine. After further addition of 0.1 part of sodium iodide, the mixture is heated in a sealed pressure reactor for 5 hours at 70 C.

succinic, tartaric, citric, ascorbic, gluconic, benzoic,

hydrin, the propylene halohydrins, allyl chloride, methallyl bromide and crotyl bromide.

My invention will-be described'in further detail by the following examples. However, these examples are not to be construed as limiting it in spirit or in scope.- ii In these "examples 'quantitiesbf materials are indicated in parts by weightand pressures in millimeters (mm.) of mercury.

and then permitted to stand at room temperature for several days. After evaporation of the butanone, the residue is taken up in dilute hydrochloric acid, washed with ether, rendered alkaline by addition of sodium carbonate and extracted with ether. This extract is dried over anhydrous potassium carbonate, filtered and evaporated to yield the N-methyl-N-benzhydrylaminoethyl ester of the N,N-diethylaminoacetic acid which is distilled at about 180-190 C. and 0.7 mm. pressure. The compound has the structural formula A mixture of 494 parts of diphenylbromomethane, 35 6 parts of N-ethyl-fi-hydroxyethylamine and 1000 parts of butanone 'is stirred for 4 hours, filtered and COIlCen- 'trated on asteam bath. The residue is made alkaline by addition of potassium carbonate and extracted with ether. The ether solution is dried over anhydrous potas- Example 6 sium carbonate, filtered and evaporated to yield N-(B-hydroxyethyl)-N-ethylbenzhyd 'ylamine which is distilled f f 2 1; 3

at about 157--165 C. and 0.7 mm. pressure. P er-ly ro-mome ane i par'ts of to 15 addfid portion-wise to a refluxing solution of 52 parts of N-n- To olut' f 102 rt f N- h (1 th 1 ;g? a 2? giii g butyl-'y-hydroxypropylam1ne 1n 20 parts of toluene. Rethiophene ree benzene there is added in the course of fllixmg conimued for 4 hoursflafter i i reaction 5 minutes, a solution of 44.8 parts of chloroacetyl chloride g 1s E thfihresultmg preclpltate 15 in 45 parts of benzene After subsidence of the initial on a lfildwlt et er. T e combined filtrates are dried exothermic reaction, the mixture is refluxed for 40 minutes, ovetr y i i fi g carbonate filtered and evap permitted to stand at room'temperature for 5 hours, Ora-e to yle y roxpmpyl)'N'n'butylbenzhydryl" diluted with water, and rendered alkaline by addition E course of 5 minute a 1 {on f 154 t f of potassium hydroxide. The organic layer is extracted 111 b l hl 3 so u 8 o with ether and the extract is dried over anhydrous potas- T 'y'c lityry e m 1 d enzeng 15 added sium carbonate, decolorized with charcoal, filtered and 15 g g 5 3 2 f y concentrated to an oil containing the chloroacetate my en y i 0 parts 9 enzene of (shydmxyethyl) N ethylbmzhydrylamine The reflux. Refiuxing is continued for 40 minutes, after which hydrochlorideobtained therefrom by treatment with alcoft". ls The 1s g alkaline by holic hydrogen-chloride melts at about185-187" C. on men 0 potassmin [OX1 e an t en enraged crystallization from a mixture of ethanol and ether. W1 th Thls.extract 1s dned over anhydrous calcium In awshieldcd pressu're reactor mixulm of 45 parts sulfate, stirred with charcoal, filtered and evaporated to of the foregoing basic chloroacetate,.20.4 parts of diethylg' i 2 g' fi amine, 21 parts of sodium iodide and 120 parts of u e W amme as a g o butanone is heated for 5 hours at 83 C., cooled and A Solution of Parts of thls ester P of freed from solvent by evaporation. The residue is taken: 25 $5 2: i s t g g gfi i fi gig f gfii g up in water, made acid by addition of dilute hydrochloric t; at g 5 hours d and freed from acid, washed with ether, rendered alkaline by addition of b b b d aqueous sodium hydroxide and extracted with ether This biltanone y evalioratlpn' e res1.ue 1s a sot e extract is dried over anhydrous potassium carbonate hydrochloric acld .Washed i ether render filtered and evaporated toyield an oily residue Upon alkahne by additlon of imute poiasslilmcarbonate and distillation at 015 mm ressure the N eth extracted with ether. This extract is dried over anhydrous hydrylaminoethyl ester of NN-diethylaminoaietic acid F i m Sulfate filtered and evaporated and the residue is collected at 158-161 C. The compound has the struc- 1S thinned at about 170-175 andp'l pressure to yield the N-butyl-N-benzhydrylaminopropyl ester of mm! formula V N,N-dimethylaminobutyric acid. This compound has the (ClHl)|N'GHr-C 0 O-CHz--CHr-NCH(CH5); structural formula (CHflr-N-CHrCHrCHg-COO-CH:-CHr-CHr-NCH(C H Hr-CHr-CHg-CH E l 4 Example 7 xamp e A mixture of 19.8 parts of N-ethyl-N-benzhydrylaminoethylester of N,N-diisopropylaminoacetic acid, 7.1 parts aminoethyl ester of N,N-diethylaminoacetic acid, 7.1 parts of iodomethane 80 Parts of butanone is heated to 80 C. for 3 hours in a sealed pressure reactor, cooled and of iodomethane and 80 parts of butanone 'is heated at 80 C. for 4 hours in a sealed pressure reactor, cooled pFrimtted to Stand under.8o.pa1:tS of ether.unt1i a and permitted to stand under 150 parts of ether at 0 C. i forms g i i l gi g defuse until aprecipitate forms. The methiodide is thus obtained whlte F i c met at s th a ter in dense white needles which melt at about 149-150 C. ffiggQfl mm butanone an 6 1. A compound of the structural formula (lower a1kyl),N-AC O OB-N-CH(G;H|), Example 5 or alkyl) wherein A is a lower alkylene radical and B is a lower chloroacetate of N-(fi-hydroxyethyl)-N-ethylbenzhydryl- Y Iadlcal Separating the Y EI P and thfi amine, 28.4 parts of diisopropylamine,'21 parts of di nitrogen atom attached thereto by at least two carbon iodide and 120 parts of butanone is heated at 80 C. for 5 hours, chilled and freed from butanone by-distillation. A compound of the Structural formula A mixture of 18.43 parts of N-ethylN-benzhydry1- In a pressure reactor a mixture of 45 parts of the The residue is taken up in water, rendered acid by addi- (lower a1kS1)2-NCHzCOO-BN-CH( 5)I tion of dilute hydrochloric acid, washed with benzene, ower alkyl) rendered alkaline by addition of concentrated aqueous wherein B is a low alkylene radical separating the sodium hydroxide solution and extracted with ether. The carboxy group and the nitrogen atom attached thereto by ether extract is dried over anhydrous potassium carbonate, at least two carbon atoms filtered and evaporated. Distillation of the oily residue A compound f the structural formula at 0.15 mm. pressure yields the N-ethyl-N-benzhydryl- (lower a1ky1)r N GH, COO CHz CHr N GH(CH) ammoethyl ester of N,N-dusopropylaminoacetic acid at about 165-173 C. The compound has the structural 4 formula (CHghN-CHr-C O0CHr-OHg-NCH(C|HJ);

( IM H 5 H:

o,m ,N-oH,-c00-onro:a,-N-on c.n.

(03010 I 1H: t 7 Hi 6. A compound of the stru ctural formula 8. 6 (lower alkyl) zNCH;-C O OCHzCHzNCH(CoH5)g (OHflPOH 7 2H N-CHg-COOCH CH lTT-CH(CH5) 5 (CHDPC 02135 7. References Cited in the file of this patent (CzHsM-N-OHz-CO0--CHzCHzN-CH(C0H5)2 UNITED STATES PATENTS 2,490,834 Rieveschl et a1. Dec. 13, 1949 2,625,547 Lawson et a1. Jan. 13, 1953 

1. A COMPOUND OF THE STRUCTURAL FROMULA 